This is a competing renewal application to continue studies on the role of sodium-hydrogen exchangers (NHE) in the gastrointestinal tract. NHE belong to a family of transport proteins involved in the electroneutral exchange of Na+ and H+. So far, nine NHEs have been cloned and characterized. NHES appears to be the predominant NHE responsible for the majority of electrolyte transport across the gastrointestinal tract, and is the target for inhibition by inflammatory cytokines resulting in diarrheal disorders. Every year, diarrhea! disorders result in the death of 5 million children below the age of 5 years. The current proposal explores a novel hypothesis to suggest that NHES is involved in the maintenance of intestinal epithelial integrity, and its loss results in alteration of intestinal epithelial barrier, allowing bacterial translocation across the gastrointestinal tract, and thus resulting in development of complications from gastroenteritis. This novel hypothesis is supported by strong preliminary data to suggest that loss of NHES, but not NHE2, results in alteration in the intestinal mucosal barrier, and extreme susceptibility to dextran sulfate-induced mucosal injury with very high mortality rate during an acute stage of inflammation in the NHES knockout mice compared to controls. Thus, our studies will address this novel hypothesis, which is supported by strong preliminary data, and will investigate three specific aims. The first specific aim is designed to explore the role of NHES in intestinal mucosal integrity. The second specific aim will explore the role of NHES in epithelial- bacterial interactions (adhesion, translocation, invasion), and the third specific aim is designed to explore the role of NHES in intestinal inflammation. These studies are likely to unravel a new role for NHES beyond its transport function of Na+ across the gastrointestinal tract. These studies have significant clinical relevance as they relate to diarrheal disorders and inflammatory bowel disease.